Insulin dependent diabetes mellitus results from an inability of b-islet cells of the pancreas to secrete sufficient insulin in response to elevation of blood glucose. At present, the principle treatment for type I diabetes is life-long supply of exogenous insulin. However, possible alternative treatments have emerged. A number of patients have been successfully rescued from insulin dependence by transplant of pancreatic islets. Despite the enormous promise of this approach there remain significant hurdles to widespread application. Among these is the limited supply of suitable material for transplant and the inability to grow and manipulate pancreatic epithelial cells in culture. In this Phase I application, we propose to devise a genoprotective protocol for expansion of normal human cells. By making a series of defined, genetic alterations, we will reversibly immortalize cells in a manner that preserves both their genomic integrity and their cellular identity. This will allow us to create clonal populations of HPE that can be expanded in culture, reverted to a normal phenotype, and tested functionally in animals. The long-term goal of the proposed program is to enable donor HPE cells to be manipulated and clonally expanded ex vivo prior to transplantation. Success would contribute a piece to the larger puzzle that must be solved before the range of patients that can be relieved of insulin dependence by islet allografting can be greatly expanded. A near-term benefit would be the derivation of clonal HPE cell lines that will enable basic research into the biology of islet cells and their progenitors. PROPOSED COMMERCIAL APPLICATIONS: The work proposed herein has numerous potential commercial applications. In the short term, the development of functional HPE cell lines would enable analysis of beta-cells and beta-cell precursors that could lead to the eventual development of biotherapeutic interventions for IDDM and NIDDM. Ultimately the approaches described herein could allow infinite expansion of material for islet autograft and allograft.